The creation of biomimetic substrates and scaffolds that support cell attachment, growth, and differentiation is a crucial component in the development of engineered tissues, and the experimental program proposed here aims to contribute to the achievement of this goal. Naturally-derived materials (e.g., collagen) have been widely explored as scaffolds for tissue engineering, but are accompanied by significant limitations (e.g., limited tailor ability and control over architecture). The use of synthetic materials that encourage cell adhesion avoids many of the limitations associated with natural materials, but such materials often require labor-intensive synthetic protocols, which hinders their widespread use as tissue engineering scaffolds. Nylon-3 copolymers are intriguing as prospective biomaterials because these polymers have a protein-mimetic backbone (2-amino acid residues) and can be assembled rapidly in functionally diverse forms; however, nylon-3 polymers have received very little attention in terms of biological applications. The PIs have recently presented preliminary results showing that nylon-3 copolymers are attractive for biomaterials applications (Lee et al., J. Am. Chem. Soc. 131:16779 (2009)). Specifically, some nylon-3 copolymers, when attached to a surface, were found to support greater cell adhesion and spreading than did positive control materials. The best of the nylon-3 copolymers supported cell attachment and spreading in the absence of serum proteins. The research proposed here builds on these initial discoveries. Our general hypothesis is that the ease with which nylon-3 copolymers can be prepared and the breadth of compositional and architectural variation that can be achieved with this system will enable us to identify examples with excellent and possibly unique characteristics as tools for tissue engineering. Moreover, these chemical features should allow us to gain a better understanding of how discrete, controlled changes in materials chemistry can control cell behavior, thereby yielding information that can be used to construct scaffolds with an optimized composition. The nylon-3 system is particularly amenable to mechanistic analysis because discrete oligomers or defined oligomer mixtures can be prepared via conventional solid-phase methods. Our long-range goal is to create new nylon-3 materials that spontaneously assemble into three- dimensional networks (hydrogels) that are physically and chemically attractive to cells. Such materials could provide new types of scaffolds for tissue engineering applications. The proposed work will focus upon the aims of: 1) Elucidating the mechanism(s) by which cells adhere to nylon-3 copolymers, and 2) Generating nylon-3 block copolymers containing segments that direct self-assembly as well as segments that control cell adhesion. PUBLIC HEALTH RELEVANCE: The generation of materials that support cell adhesion and growth is important in the construction of engineered environments that are designed to replace damaged or diseased tissues. In this proposal, we aim to create and characterize new types of biomaterials that are synthetic in structure, but that can behave in a biomimetic manner. These biomaterials will allow us to better understand the manner in which cells interact with and receive information from their surroundings, and will be used to create a new type of 3-D scaffold material for use in regenerative medicine applications.